3-Azido-tetrahydrofuran carboxylates as scaffolds for oligomers of beta-amino-THF carboxylic acids

Thesis

This thesis describes investigations into the synthesis and secondary structural properties of novel carbohydrate-derived peptidomimetics.

The syntheses from diacetone-D-glucose of five diastereomeric 3-azido-tetrahydrofuran carboxylates are described. These highly functionalised β-amino acid equivalents are accessed via the diacetone-3-azido-3-deoxy sugars and 3-azido-3-deoxy-1,4-lactones. An acid-catalysed rearrangement results in the formation of the tetrahydrofuran ring with the protected amine functionality already in place in a position β- to the carboxylate group.

Attempts to synthesise "carbopeptoids" via various oligomerisation strategies, including three novel approaches to oligomerisation, are delineated. The first approach attempted involves an iterative addition of a bicyclic lactone, which acts as the activated acid component, to the substrate containing an amine functionality. A new solid-phase oligomerisation strategy, whereby the coupling reagent is tethered to the polystyrene support and the substrates remain in solution, is described. The third attempted novel oligomerisation strategy involves activation by microwave irradiation, in the absence of coupling reagents. The conventional coupling using a carbodiimide coupling reagent proves to be a highly efficient means to access oligomers up to six residues in length, and is utilised for the synthesis of the homooligomers of four diastereomeric carbohydrate-derived β-amino acids.

The prospect that the carbopeptoids may emulate the helical conformations reported for closely related 2-aminocyclopentanecarboxylic acid oligomers is investigated. Different methods of spectroscopic analysis of the tetrameric and hexameric oligomers are discussed. Circular dichroism spectroscopy provides a rapid diagnostic tool for the investigation of peptide bond orientations and forms the basis for a postulation on a possible stabilised hydrogen-bonding secondary structural conformation in two tetrameric species. Several nuclear magnetic resonance spectroscopic experiments are performed, enabling the assignment of each signal in the proton spectrum for a hexameric oligomer. However the resulting data does not provide sufficient evidence for a well-defined secondary structural motif, and so the potential conformational preference postulated on the basis of circular dichroism spectroscopy is not confirmed.

Authors: Marsh, P

• Peer review status: Peer reviewed
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford